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Marie B Demay - One of the best experts on this subject based on the ideXlab platform.
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vitamin d receptor is essential for normal keratinocyte stem cell functIon
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Luisella Cianferotti, Megan K Cox, Kristi Skorija, Marie B DemayAbstract:The major physiological role of the vitamin D receptor (VDR) is the maintenance of mineral Ion Homeostasis. MutatIon of the VDR, in humans and mice, results in alopecia. Unlike the effects of the VDR on mineral Ion Homeostasis, the actIons of the VDR that prevent alopecia are ligand-independent. Although absence of the VDR does not prevent the development of a keratinocyte stem cell niche in the bulge regIon of the hair follicle, it results in an inability of these stem cells to regenerate the lower portIon of the hair follicle in vivo and impairs keratinocyte stem cell colony formatIon in vitro. VDR ablatIon is associated with a gradual decrease in keratinocyte stem cells, accompanied by an increase in sebaceous activity, a phenotype analogous to that seen with impaired canonical Wnt signaling. Transient gene expressIon assays demonstrate that the cooperative transcriptIonal effects of β-catenin and Lef1 are abolished in keratinocytes isolated from VDR-null mice, revealing a role for the unliganded VDR in canonical Wnt signaling. Thus, absence of the VDR impairs canonical Wnt signaling in keratinocytes and leads to the development of alopecia due to a defect in keratinocyte stem cells.
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hypophosphatemia leads to rickets by impairing caspase mediated apoptosis of hypertrophic chondrocytes
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Yves Sabbagh, Thomas O Carpenter, Marie B DemayAbstract:Rickets is seen in associatIon with vitamin D deficiency and in several genetic disorders associated with abnormal mineral Ion Homeostasis. Studies in vitamin D receptor (VDR)-null mice have demonstrated that expansIon of the late hypertrophic chondrocyte layer, characteristic of rickets, is secondary to impaired apoptosis of these cells. The observatIon that normalizatIon of mineral Ion Homeostasis in the VDR-null mice prevents rachitic changes suggests that rickets is secondary to hypocalcemia, hypophosphatemia, or hyperparathyroidism, rather than impaired VDR actIon. To determine which of these abnormalities is responsible for impaired chondrocyte apoptosis and subsequent rachitic changes, two additIonal models were examined: diet-induced hypophosphatemia/hypercalcemia and hypophosphatemia secondary to mutatIons in the Phex gene. The former model is associated with suppressed parathyroid hormone levels as a consequence of hypercalcemia. The latter model demonstrates normal calcium and parathyroid hormone levels, but 1,25-dihydroxyvitamin D levels that are inappropriately low for the degree of hypophosphatemia. Our studies demonstrate that normal phosphorus levels are required for growth plate maturatIon and implicate a critical role for phosphate-regulated apoptosis of hypertrophic chondrocytes via activatIon of the caspase-9-mediated mitochondrial pathway.
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rescue of the skeletal phenotype of vitamin d receptor ablated mice in the setting of normal mineral Ion Homeostasis formal histomorphometric and biomechanical analyses
Endocrinology, 1999Co-Authors: Michael Amling, Roland Baron, Matthias Priemel, Timothy Holzmann, Kelli Chapin, Johannes M Rueger, Marie B DemayAbstract:1,25-Dihydroxyvitamin D3 has been shown to play an important role in vitro in regulating osteoblast gene transcriptIon and promoting osteoclast differentiatIon. To address the role of the vitamin D receptor (VDR) in skeletal Homeostasis, formal histomorphometric analyses were performed in VDR null mice in the setting of impaired mineral Ion Homeostasis as well as in VDR null mice in whom normal mineral Ion Homeostasis had been preserved. In hypocalcemic VDR null mice, there was an increase in bone volume as a result of a dramatic increase in osteoid. There was also an increase in the number of osteoblasts without a significant change in the number of osteoclasts. ExaminatIon of the growth plate revealed marked disorganizatIon, with an increase in vascularity and matrix. Biomechanical parameters demonstrated increased bone fragility in the hypocalcemic VDR null mice. In the VDR ablated mice in whom normal mineral Ion Homeostasis had been preserved, none of these measurements was significantly different fro...
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normalizatIon of mineral Ion Homeostasis by dietary means prevents hyperparathyroidism rickets and osteomalacia but not alopecia in vitamin d receptor ablated mice1
Endocrinology, 1998Co-Authors: Yan Chun Li, Roland Baron, Michael Amling, Matthias Priemel, Alison E Pirro, Jennifer Meuse, G Delling, Marie B DemayAbstract:1,25-Dihydroxyvitamin D3 plays a major role in intestinal calcium transport. To determine what phenotypic abnormalities observed in vitamin D receptor (VDR)-ablated mice are secondary to impaired intestinal calcium absorptIon rather than receptor deficiency, mineral Ion levels were normalized by dietary means. VDR-ablated mice and control littermates were fed a diet that has been shown to prevent secondary hyperparathyroidism in vitamin D-deficient rats. This diet normalized growth and random serum Ionized calcium levels in the VDR-ablated mice. The correctIon of Ionized calcium levels prevented the development of parathyroid hyperplasia and the increases in PTH messenger RNA synthesis and in serum PTH levels. VDR-ablated animals fed this diet did not develop rickets or osteomalacia. However, alopecia was still observed in the VDR-ablated mice with normal mineral Ions, suggesting that the VDR is required for normal hair growth. This study demonstrates that normalizatIon of mineral Ion Homeostasis can prev...
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normalizatIon of mineral Ion Homeostasis by dietary means prevents hyperparathyroidism rickets and osteomalacia but not alopecia in vitamin d receptor ablated mice
Endocrinology, 1998Co-Authors: Roland Baron, Michael Amling, Matthias Priemel, Alison E Pirro, Jennifer Meuse, G Delling, Marie B DemayAbstract:1,25-Dihydroxyvitamin D3 plays a major role in intestinal calcium transport. To determine what phenotypic abnormalities observed in vitamin D receptor (VDR)-ablated mice are secondary to impaired intestinal calcium absorptIon rather than receptor deficiency, mineral Ion levels were normalized by dietary means. VDR-ablated mice and control littermates were fed a diet that has been shown to prevent secondary hyperparathyroidism in vitamin D-deficient rats. This diet normalized growth and random serum Ionized calcium levels in the VDR-ablated mice. The correctIon of Ionized calcium levels prevented the development of parathyroid hyperplasia and the increases in PTH messenger RNA synthesis and in serum PTH levels. VDR-ablated animals fed this diet did not develop rickets or osteomalacia. However, alopecia was still observed in the VDR-ablated mice with normal mineral Ions, suggesting that the VDR is required for normal hair growth. This study demonstrates that normalizatIon of mineral Ion Homeostasis can prevent the development of hyperparathyroidism, osteomalacia, and rickets in the absence of the genomic actIons of 1,25-dihydroxyvitamin D3.
Johannes Overgaard - One of the best experts on this subject based on the ideXlab platform.
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preservatIon of potassium balance is strongly associated with insect cold tolerance in the field a seasonal study of drosophila subobscura
Biology Letters, 2016Co-Authors: Heath A Macmillan, Mads Fristrup Schou, Torsten Nygaard Kristensen, Johannes OvergaardAbstract:There is interest in pinpointing genes and physiological mechanisms explaining intra- and interspecific variatIons in cold tolerance, because thermal tolerance phenotypes strongly impact the distributIon and abundance of wild animals. Laboratory studies have highlighted that the capacity to preserve water and Ion Homeostasis is linked to low temperature survival in insects. It remains unknown, however, whether adaptive seasonal acclimatizatIon in free-ranging insects is governed by the same physiological mechanisms. Here, we test whether cold tolerance in field-caught Drosophila subobscura is high in early spring and lower during summer and whether this transitIon is associated with seasonal changes in the capacity of flies to preserve water and Ion balance during cold stress. Indeed, flies caught during summer were less cold tolerant, and exposure of these flies to sub-zero temperatures caused a loss of haemolymph water and increased the concentratIon of K+ in the haemolymph (as in laboratory-reared insects). This pattern of Ion and water balance disruptIon was not observed in more cold-tolerant flies caught in early spring. Thus, we here provide a field verificatIon of hypotheses based on laboratory studies and conclude that the ability to maintain Ion Homeostasis is important for the ability of free-ranging insects to cope with chilling.
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why do insects enter and recover from chill coma low temperature and high extracellular potassium compromise muscle functIon in locusta migratoria
The Journal of Experimental Biology, 2014Co-Authors: Anders Findsen, Thomas Holm Pedersen, Asbjorn Graver Petersen, Ole Baekgaard Nielsen, Johannes OvergaardAbstract:When exposed to low temperatures, many insect species enter a reversible comatose state (chill coma), which is driven by a failure of neuromuscular functIon. Chill coma and chill coma recovery have been associated with a loss and recovery of Ion Homeostasis (particularly extracellular [K+], [K+]o) and accordingly onset of chill coma has been hypothesized to result from depolarizatIon of membrane potential caused by loss of Ion Homeostasis. Here, we examined whether onset of chill coma is associated with a disturbance in Ion balance by examining the correlatIon between disruptIon of Ion Homeostasis and onset of chill coma in locusts exposed to cold at varying rates of cooling. Chill coma onset temperature changed maximally 1°C under different cooling rates and marked disturbances of Ion Homeostasis were not observed at any of the cooling rates. In a second set of experiments, we used isolated tibial muscle to determine how temperature and [K+]o, independently and together, affect tetanic force productIon. Tetanic force decreased by 80% when temperature was reduced from 23°C to 0.5°C, while an increase in [K+]o from 10 mmol l−1 to 30 mmol l−1 at 23°C caused a 40% reductIon in force. Combining these two stressors almost abolished force productIon. Thus, low temperature alone may be responsible for chill coma entry, rather than a disruptIon of extracellular K+ Homeostasis. As [K+] also has a large effect on tetanic force productIon, it is hypothesized that recovery of [K+]o following chill coma could be important for the time to recovery of normal neuromuscular functIon.
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rapid cold hardening improves recovery of Ion Homeostasis and chill coma recovery time in the migratory locust locusta migratoria
The Journal of Experimental Biology, 2013Co-Authors: Anders Findsen, Jonas Lembcke Andersen, Sofia Calderon, Johannes OvergaardAbstract:Chill tolerance of insects is defined as the ability to tolerate low temperature under circumstances not involving freezing of intracellular or extracellular fluids. For many insects chill tolerance is crucial for their ability to persist in cold environments and mounting evidence indicates that chill tolerance is associated with the ability to maintain Ion and water Homeostasis, thereby ensuring muscular functIon and preventing chill injury at low temperature. The present study describes the relatIonship between muscle and haemolymph Ion Homeostasis and time to regain posture following cold shock (CS, 2 h at −4°C) in the chill-susceptible locust Locusta migratoria . This relatIonship was examined in animals with and without a prior rapid cold-hardening treatment (RCH, 2 h at 0°C) to investigate the physiological underpinnings of RCH. CS elicited a doubling of haemolymph [K+] and this disturbance was greater in locusts pre-exposed to RCH. Recovery of Ion Homeostasis was, however, markedly faster in RCH-treated animals, which correlated well with whole-organism performance as hardened individuals regained posture faster than non-hardened individuals following CS. The present study indicates that loss and recovery of muscular functIon are associated with the resting membrane potential of excitable membranes as attested by the changes in the equilibrium potential for K+ ( E K) following CS. Both hardened and non-hardened animals regained movement once K+ Homeostasis had recovered to a fixed level ( E K≈−41 mV). RCH is therefore not associated with altered sensitivity to Ion disturbance but instead is correlated to a faster recovery of haemolymph [K+]. * [ X ]i : concentratIon of Ion X in the intracellular fluid (muscle) [ X ]o : concentratIon of Ion X in the extracellular fluid (haemolymph) CS : cold shock E K : equilibrium potential for K+ E Na : equilibrium potential for Na+ LT50 : temperature at which 50% of the animals are dead RCH : rapid cold hardening V m : membrane potential
J D Gantz - One of the best experts on this subject based on the ideXlab platform.
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effects of brief chilling and desiccatIon on Ion Homeostasis in the central nervous system of the migratory locust locusta migratoria
Comparative Biochemistry and Physiology A-molecular & Integrative Physiology, 2020Co-Authors: J D Gantz, Kristin E Spong, Erik A Seroogy, Meldrum R Robertson, Richard E LeeAbstract:Abstract In insects, chilling, anoxia, and dehydratIon are cues to trigger rapid physiological responses enhancing stress tolerance within minutes. Recent evidence suggests that responses elicited by different cues are mechanistically distinct from each other, though these differences have received little attentIon. Further, the effects are not well studied in neural tissue. In this study, we examined how brief exposure to desiccatIon and chilling affect Ion homeostatic mechanisms in metathoracic ganglIon of the migratory locust, Locusta migratoria. Both desiccatIon and chilling enhanced resistance to anoxia, though only chilling hastened recovery from anoxic coma. Similarly, only chilling enhanced resistance to pharmacological perturbatIon of neuronal Ion Homeostasis. Our results indicate that chilling and desiccatIon trigger mechanistically distinct responses and, while both may be important for neuronal Ion Homeostasis, chilling has a larger effect on this tissue. Summary statement This is one of few studies to demonstrate the importance of the central nervous system in rapid acclimatory responses in insects.
Hannes Vogel - One of the best experts on this subject based on the ideXlab platform.
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altered micos morphology and mitochondrial Ion Homeostasis contribute to poly gr toxicity associated with c9 als ftd
Cell Reports, 2020Co-Authors: Ishaq Tantray, Diego De Stefani, Andrea Mattarei, Gopinath Krishnan, Fenbiao Gao, Hannes VogelAbstract:Amyotrophic lateral sclerosis (ALS) manifests pathological changes in motor neurons and various other cell types. Compared to motor neurons, the contributIon of the other cell types to the ALS phenotypes is understudied. G4C2 repeat expansIon in C9ORF72 is the most common genetic cause of ALS along with frontotemporal dementia (C9-ALS/FTD), with increasing evidence supporting repeat-encoded poly(GR) in disease pathogenesis. Here, we show in Drosophila muscle that poly(GR) enters mitochondria and interacts with components of the Mitochondrial Contact Site and Cristae Organizing System (MICOS), altering MICOS dynamics and intra-subunit interactIons. This impairs mitochondrial inner membrane structure, Ion Homeostasis, mitochondrial metabolism, and muscle integrity. Similar mitochondrial defects are observed in patient fibroblasts. Genetic manipulatIon of MICOS components or pharmacological restoratIon of Ion Homeostasis with nigericin effectively rescue the mitochondrial pathology and disease phenotypes in both systems. These results implicate MICOS-regulated Ion Homeostasis in C9-ALS pathogenesis and suggest potential new therapeutic strategies.
Michael Amling - One of the best experts on this subject based on the ideXlab platform.
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rescue of the skeletal phenotype of vitamin d receptor ablated mice in the setting of normal mineral Ion Homeostasis formal histomorphometric and biomechanical analyses
Endocrinology, 1999Co-Authors: Michael Amling, Roland Baron, Matthias Priemel, Timothy Holzmann, Kelli Chapin, Johannes M Rueger, Marie B DemayAbstract:1,25-Dihydroxyvitamin D3 has been shown to play an important role in vitro in regulating osteoblast gene transcriptIon and promoting osteoclast differentiatIon. To address the role of the vitamin D receptor (VDR) in skeletal Homeostasis, formal histomorphometric analyses were performed in VDR null mice in the setting of impaired mineral Ion Homeostasis as well as in VDR null mice in whom normal mineral Ion Homeostasis had been preserved. In hypocalcemic VDR null mice, there was an increase in bone volume as a result of a dramatic increase in osteoid. There was also an increase in the number of osteoblasts without a significant change in the number of osteoclasts. ExaminatIon of the growth plate revealed marked disorganizatIon, with an increase in vascularity and matrix. Biomechanical parameters demonstrated increased bone fragility in the hypocalcemic VDR null mice. In the VDR ablated mice in whom normal mineral Ion Homeostasis had been preserved, none of these measurements was significantly different fro...
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normalizatIon of mineral Ion Homeostasis by dietary means prevents hyperparathyroidism rickets and osteomalacia but not alopecia in vitamin d receptor ablated mice1
Endocrinology, 1998Co-Authors: Yan Chun Li, Roland Baron, Michael Amling, Matthias Priemel, Alison E Pirro, Jennifer Meuse, G Delling, Marie B DemayAbstract:1,25-Dihydroxyvitamin D3 plays a major role in intestinal calcium transport. To determine what phenotypic abnormalities observed in vitamin D receptor (VDR)-ablated mice are secondary to impaired intestinal calcium absorptIon rather than receptor deficiency, mineral Ion levels were normalized by dietary means. VDR-ablated mice and control littermates were fed a diet that has been shown to prevent secondary hyperparathyroidism in vitamin D-deficient rats. This diet normalized growth and random serum Ionized calcium levels in the VDR-ablated mice. The correctIon of Ionized calcium levels prevented the development of parathyroid hyperplasia and the increases in PTH messenger RNA synthesis and in serum PTH levels. VDR-ablated animals fed this diet did not develop rickets or osteomalacia. However, alopecia was still observed in the VDR-ablated mice with normal mineral Ions, suggesting that the VDR is required for normal hair growth. This study demonstrates that normalizatIon of mineral Ion Homeostasis can prev...
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normalizatIon of mineral Ion Homeostasis by dietary means prevents hyperparathyroidism rickets and osteomalacia but not alopecia in vitamin d receptor ablated mice
Endocrinology, 1998Co-Authors: Roland Baron, Michael Amling, Matthias Priemel, Alison E Pirro, Jennifer Meuse, G Delling, Marie B DemayAbstract:1,25-Dihydroxyvitamin D3 plays a major role in intestinal calcium transport. To determine what phenotypic abnormalities observed in vitamin D receptor (VDR)-ablated mice are secondary to impaired intestinal calcium absorptIon rather than receptor deficiency, mineral Ion levels were normalized by dietary means. VDR-ablated mice and control littermates were fed a diet that has been shown to prevent secondary hyperparathyroidism in vitamin D-deficient rats. This diet normalized growth and random serum Ionized calcium levels in the VDR-ablated mice. The correctIon of Ionized calcium levels prevented the development of parathyroid hyperplasia and the increases in PTH messenger RNA synthesis and in serum PTH levels. VDR-ablated animals fed this diet did not develop rickets or osteomalacia. However, alopecia was still observed in the VDR-ablated mice with normal mineral Ions, suggesting that the VDR is required for normal hair growth. This study demonstrates that normalizatIon of mineral Ion Homeostasis can prevent the development of hyperparathyroidism, osteomalacia, and rickets in the absence of the genomic actIons of 1,25-dihydroxyvitamin D3.
